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Blood, 1 November 2004, Vol. 104, No. 9, pp. 2794-2800.
Prepublished online as a Blood First Edition Paper on June 29, 2004; DOI 10.1182/blood-2003-11-3789.
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IMMUNOBIOLOGY
Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution
Terry J. Fry,
Manoj Sinha,
Matthew Milliron,
Yu-Waye Chu,
Veena Kapoor,
Ronald E. Gress,
Elaine Thomas, and
Crystal L. Mackall
From the Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and Immunex, Seattle, WA.
Despite recent progress in our understanding of the biology of T-cell homeostasis, clinically available therapies to substantially improve immune reconstitution in patients sustaining T-cell depletion are lacking. T cells are regenerated via a dynamic interplay between thymopoiesis and thymic-independent homeostatic peripheral expansion (HPE). Using athymic mice subjected to T-cell depletion, we observed that HPE is critically dependent on dendritic cells (DCs) for presentation of antigen, raising the possibility that the availability of DCs might be limiting in vivo for HPE to occur efficiently. Indeed, flt3 ligand (flt3L) treatment of athymic mice subjected to T-cell depletion (without DC depletion) substantially enhanced HPE and improved immune competence. Following bone marrow transplantation (BMT) in athymic hosts, both dendritic cells and T cells were profoundly depleted and flt3L therapy restored DC numbers and enhanced HPE. In addition, thymus-bearing BMT recipients treated with flt3L regenerated increased numbers of thymic-dependent progeny with increased numbers of T-cell receptor excision circle (TREC)-positive T cells, indicating increased thymopoiesis. Therefore, flt3L is a potent immunorestorative agent that enhances both thymic-dependent and thymic-independent pathways of T-cell regeneration. (Blood. 2004;104:2794-2800)
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